1. Field of the Invention
A generator that may be loaded with a parent isotope, which is retained on the generator and readily releases the daughter isotope formed by the decay of the parent and methods of use and construction thereof.
2. Background of the Related Art
Rhenium-188 (188Re, an isotope of rhenium having 75 protons and 113 neutrons in its nucleas) is chemically very similar to the well known and widely utilized isotope technetium-99m (99mTc), but while 99mTc is a gamma ray (γ) emitter that is useful for single photon emission computed tomography (SPECT) imaging, 188Re is a beta emitter (β−) producing a 2.12 MeV electron as it decays to stable 188Os. This high energy beta emission and short half life (16.9 hours) makes 188Re an excellent isotope for radiotherapeutic applications. 90Y, an isotope with a similar beta emission (2.28 MeV) already has FDA approval for the treatment of various cancers (e.g., non-Hodgkin's lymphoma) and it is anticipated that 188Re can be used in a similar role and open up access to additional coordinating groups and antibodies.
90Y has a half life of approximately 64 hours which means that it can be produced at a central location and distributed to clinics and research establishments. However, 188Re has a half life of only 16.9 hours which is too short for the isotope to be conveniently shipped, and thus means that it must be generated at the site of use. As a consequence, the development of a commercial, reliable generator is essential to ensure that the clinical possibilities of this isotope are fully realized. This short half-life also means that the activity of the isotope rapidly dies away, reducing the chance for damage to other areas of the body if the targeting agent to which the isotope has been attached breaks down, releasing the isotope into other areas of the body where it isn't desired.
Knapp describes a 188Re generator having a dual column system that retains a 188W “cow” on a chromatographic alumina column. The 188Re is eluted using a saline solution, and the saline solution converted to the pure perrhenic acid by a subsequent ion exchange using a cation exchange column. This is at best a two step process, with the potential for yield loss in the ion exchange step. Alumina is a poor ion exchange material with a low ion exchange capacity, poor selectivity, and limited stability. This may lead to premature column blocking and the release of aluminum, or even the parent 188W, into the 188Re product.
A “one pot” synthesis has been developed for a gel type generator, with the cow retained on a gel column produced by dissolving the target under carefully controlled conditions. This method is described as applicable to both 188Re/188W and 99mTc/99Mo. The method has a limitation in that the start of 188W breakthrough occurs after only 5 to 10 elutions, far too few for a practical generator.
A gas phase method has been described for separating 188Re from 188W based on the volatility of HReO4. In this approach, described as thermochromatographic separation, the irradiated 186W target is heated to ˜1,000° C. to volatilize the Re containing species, which is carried to a colder region in a stream of moist air. The advantage of this method is that the 186W enriched target can be reused. The disadvantage is that the high temperatures required by this process can potentially volatilize other, less desirable materials out of the target as well. The extreme conditions required also means that this method is clearly unsuitable for the on site production of 188Re, which is essential given the short half life.
Khalid et al. published a study in which they examined a variety of materials with the potential of serving as the support for the 188W cow in a 188Re generator. They examined both organic and inorganic materials including charcoal, silica-gel, alumina, lead, a number of transition metal oxides, and conventional ion exchange resins. None of these materials were found to be very effective at sequestering 188W. In most cases the tungsten and rhenium affinities were only a factor of 10 to 100 different, inadequate for achieving a good separation. The best results reported were achieved at low pH, complicating the use of the perrhenate in complexation processes.
Most of the well known inorganic ion exchange materials, such as zeolites, titanium phosphates, and zirconium phosphates, are cation exchangers. Only a few materials are known that are anion exchangers, but an anion exchanger is required to sequester tungsten-188 because in aqueous systems the stable form of tungsten is the tungstate anion (WO4=) or its anionic derivatives.
Most inorganic materials used as anion exchangers can be generally classed as hydrous metal oxides (e.g., alumina, zirconia, etc.). These materials can be considered to consist of discrete metal oxide clusters covered by surface hydroxyl groups. At low pH, these hydroxide groups become protonated and the material develops a positive charge. Anions are thus absorbed to maintain electroneutrality. At high pH, the hydroxyl groups lose protons and the material becomes negatively charged and acts as a cation exchanger. Thus, this class of materials are effectively amphoteric and can be either anion or cation exchangers, depending upon the pH. Another disadvantage of these materials is that they are poorly characterized and almost impossible to reproducibly synthesize making them poor candidates for use in a system producing isotopes for the treatment of human patients. Radiation stability is also an issue and physical breakdown of the material can cause problems in generator operation.
Therefore, there is a need for improved methods, apparatuses, and compositions for separating rhenium-188 from its parent tungsten-188. It would be desirable if the compositions were highly radiation resistant, thermally stable, chemically stable, and non-toxic. It would be even more desirable if the compositions and methods provided very high affinities for the parent as opposed to the daughter isotope.